Indoline-2-one derivatives and preparation thereof

ABSTRACT

Indoline-2-one derivatives, more particularly, 1-benzyl-3substituted or unsubstituted-aminomethyl-3-hydroxy-indoline-2-one derivatives and their pharmacologically acceptable salts as well as the methods for synthesis thereof. The compounds are new and possess strong analgesic and anti-inflammatory activities with low toxicity and accordingly they are useful for therapeutic purposes.

finite States irose et al.

atent 1 [54] INDOLINE-Z-ONE DERIVATIVES AND PREPARATION THEREOF [75]Inventors: Noriyasu Hirose; Shigeru Souda,

both of Tokyo, Japan [30] Foreign Application Priority Data Sept. 30,1969 Japan ..44/77438 Sept. 30, 1969 Japan ..44/77439 Sept. 30, 1969Japan ..44/77440 Sept. 30, 1969 Japan ..44/7744l [52] U.S. Cl ..260/325,424/274 [51] Int. Cl. ..C07d 27/40 [58] Field of Search ..260/325 [56]References Cited UNITED STATES PATENTS 2,759,935 8/1956 Speeter..260/247.2

OTHER PUBLICATIONS l-lallmann, Berichte 95: 1138-43 (1962) PrimaryExaminer-Donald G. Daus Assistant ExaminerJoseph A. NarcavageAtt0rney-l-lenry T. Burke, Robert Scobey, Robert S. Dunham, P. E.Henninger, Lester W. Clark, Gerald L. Griffin, Thomas F. Moran, R.Bradlee Boal and Christopher C. Dunham [57] ABSTRACT Indoline-Z-onederivatives, more particularly, 1- benzyl-3-substituted orunsubstituted-aminomethyl-3- hydroxy-indoline-Z-one derivatives andtheir pharmacologically acceptable salts as well as the methods forsynthesis thereof. The compounds are new and possess strong analgesicand anti-inflammatory activities with low toxicity and accordingly theyare useful for therapeutic purposes.

6 Claims, No Drawings lNDOLlNE-2-ONE DERIVATIVES AND PREPARATION THEREOFThis invention relates to indoline-2-one derivatives, new substances,and synthetic preparation thereof. More particularly the presentinvention is concerned with l-benzyl-3-substituted orunsubstitutedaminomethyl-3-hydroxyindoline-2-one derivatives and theirpharmacologically acceptable salts as well as the methods for synthesisthereof.

The new indoline-Z-one derivatives with which the present invention isconcerned are represented by the formula wherein R is H, --CH(CH loweralkylcarbonyl, benzoyl or CONH group and X is H or halogen atom.

It has been found that the compounds of formula (I) of the presentinvention exhibit outstanding analgesic and anti-inflammatory activitieswith low human toxicity and therefore are useful for therapeuticpurposes.

The pharmacological activities of the new compounds as proved by theanimal experiment described below are superior to those exhibited by thecompounds of pyrine series such as, for example, aminopyrine andphenylbutazone which have popularly been employed in the clinical field.

The animal experiment was carried out on mice to evaluate the inhibitionactivity of the compounds against the stretching caused byintraperitoneal injection of a 0.5 percent aqueous acetic acid solution.At the same time control tests were also carried out in the same mannerutilizing aminopyrine and phenylbutazone.

Sixty adult mice were divided into two groups, Group A and Group B.

Each of Groups A and B was further divided into Subgroups A A A A A andA and Sub-groups B,, B B B B and B.,, the respective Sub-groupsinvolving five animals. To each of the five animals of the respectiveSub-groups A to A inclusive was intraperitoneally administrated 25 mg/kgof the compounds a, b, c, d, e and f, while to each of the five animalsof the respective Sub-groups B to B, inclusive was intraperitoneallyadministrated 50 mg/kg of the compounds a, b, c, d, e andf. Thecompounds 0, b, c, and d belong to the indoline-Z-one compounds of thegeneral formula (1) according to the present invention and containrespectively the following substituents.

Compounds I R X a C-- H b --CONH, H c COHN, Cl

Compound e is aminopyrine having the formula and compoundfisphenylbutazone having the formula All the compounds under test includingthose of the 'present invention and of the control were providedrespectively in a form of a Tyrode solution. Analgesic activities of thecompounds under test were evaluated and ranked as perfect whenstretching on an animal previously treated with the compound under testcould not be observed upon subsequent administration of acetic acidsolution.

The results observed are tabulated:

As is evident from the above data, compounds a to 11 inclusive of thepresent invention and especially compound c which contains thesubstituents R=---CONl-l and X=Cl show a notable analgesic activity.

It has been found furthermore that compounds according to the presentinvention possess a markedly low toxicity. LD: 300 mg/kg was observedwhen compound c was intraperitoneally administrated to mice. Inconsideration of the said LD value as compared with LD mg/kg ofphenylbutazone which is known to be less toxic than aminopyrine, it isapparent that the new compound of the present invention can be used asmedicament without fear of harmful toxicity.

The new compounds can be obtained by catalytic reduction of selectedl-benzyl-3-hydroxy-3- nitromethyl-indoline-2-one compounds, the lattercompound being obtainable by the reaction of l-benzylisatin andnitromethane.

1n a particular case, the compound of the formula (1) wherein thesubstituent R is --Cl-l(CH can advantageously be obtained in a singlestep by carrying out the catalytic reduction of the abovementionedlbenzyl-3-hydroxy-3-nitromethyl-indoline-Z-one compound in excess amountof acetone utilizing a catalyst such as platinum oxide, Raney Nickel, orpalladiumcarbon. The excess amount of the acetone serves partly as oneof the reactants entering into formation of the intended final productand partly as the reaction medium of the system.

Ethyl acetate was found to be the most preferable solvent for carryingout recrystallization of the resulting reaction product.

Alternatively, in case a compound embraced by the formula (I) whereinthe substituent R is other than Cl-l(CH;,) is desired, the said compoundmay advantageously be obtained first by catalytic reduction of the1-benzyl-3-hydroxy-3-nitromethyl-indoline-2-one compound by the aid of acatalyst such as aforementioned in a solvent inactive to the amino groupin the resulting reduction product, i. e., the compound of the formula(1) wherein R is H. The resulting compound, if desired, may furtherbeconverted into a compound containing a substituent -CONH for R, forexample, by subjecting the former compound toreact with an alkali metalcyanate such for example potassium or sodium cyanate.

Alternatively, if a corresponding compound containing a loweralkylcarbonyl or benzyl group for the substituent R, for example, isdesired, said compound may be obtained by reacting the aforementionedcompound, wherein the radical R is H, with a desired lower alkylcarbonylhalogenide or benzoyl halogenide.

Typical 1-benzyl-3-hydroxy-3-nitromethyl-indoline- 2-one compounds whichcan be employed as starting material to carry out the process of thepresent invention include1-benzyl-3-hydroxy-3-nitromethyl-indoline-2-one melting at l25127C. andl-(pchlorobenzyl)-3-hydroxy-3-nitromethyl-indoline-Z-one melting atl01-102C.

The following examples are given to illustrate the process of theinvention, but the invention is not construed as to be restricted to theexamples.

EXAMPLE 1 Preparation of1-benzyl-3-hydroxy-3-isopropylaminomethyl-indoline-Z-one 6 Grams of1-benzyl-3-hydroxy-3-nitromethyl-indoline-2-one, 0.2 grams of platinumoxide as catalyst and 200 ml of acetone were charged in an autoclave. Acatalytic reduction under high pressure of the content of the autoclavewas carried out with the initial pressure of 60 atms. of gaseoushydrogen and the reaction temperature of 80C. for a time sufficient tocomplete the reduction. After that time, the reaction mixture was takenup and filtered to remove the spent catalyst. By concentrating thefiltrate, there was obtained an oily substance which was dissolved in asuitable amount of ethyl acetate. The crystalline substance separatedout was recovered and recrystallized from ethyl acetate colorlessneedles melting at 115116C. were obtained.

Elementary analysis of the product gave:

C H N Calculated as C,, H N, 0,; 73.52 7.14 9.03 Found 73.82 7.34 8.72

EXAMPLE 2 Preparation of l-(p-chlorobenzyl)-3-hydroxy-3-isopropylaminomethyl-indoline-Z-one 6.6 Grams of1-(p-chlorobenzyl)-3-hydroxy-3- nitromethyl-indoline-Z-one, 0.3 grams ofpalladium black carried on carbon and 200 ml of acetone were charged inan autoclave and further worked up in accordance with the procedure ofthe preceding example.

There were obtained colorless needles melting at C.

Elementary analysis of the product gave:

C H N Calculated as C H CIN, 0,: 66.18 6.14 8.12 Found 66.09 5.90 8.13

EXAMPLE 3 Preparation of l-benzyl-3-aminomethyl-3-hydroxyindoline-2-one6 Grams of 1-benzyl-3-hydroxy-3-nitromethy1-indoline-2-one, 3 ml ofacetic acid, 0.1 gram of platinum oxide and 200 ml of ethanol werecharged in an autoclave. The high pressure reduction of the content ofthe autoclave with an initial gaseous hydrogen pressure at 60 atms. wascarried out for the time sufficient to complete the reduction. Thereaction mixture was then filtered to remove the spent catalyst, and thefiltrate was concentrated by evaporation under reduced pressure. Adilute aqueous solution of caustic alkali was added to the concentrateto isolate the resulting amine which was extracted with ether.

By passing dry hydrogen chloride through the etheral extract, thehydrochloride of the contemplated compound was crystallized out whichwas recovered by filtration. The crystalline substance was purified byrecrystallization from isopropanol.

The hydrochloride of the compound had a melting point of 176C.

Elementary analysis of the product gave:

C H N Calculated as C H N, O,'HC1: 63.04 5.62 9.20 Found 62.97 5.67 9.31

EXAMPLE 4 Preparation of 1-(p-chlorobenzyl)-3-aminomethyl-3-hydroxy-indoline-Z-one 3.3 Grams of 1-(p-chlorobenzyl)-3-hydroxy-3-nitromethyl-indoline-Z-one, 0.15 grams of platinum oxide as catalyst and200 ml of ethanol were charged together in a catalytic reduction deviceto be operated at ordinary pressure.

A current of hydrogen was passed through the device until thetheoretical quantity of the hydrogen was consumed. The reduction productwas further worked up in accordance with the procedure as mentioned inExample 3.

The product thus obtained as hydrochloride had a melting point ofl93l95C.

Elementary analysis of the product gave:

C H N Calculated as C H Cl N 0,-HCl: 56.64 4.76 8.26 Found 56.60 4.758.48

EXAMPLE 5 Preparation of l-benzyl-3-carbamylaminomethyl-3-hydroxy-indoline-Z-one 3.0 Grams of1-benzyl-3-aminomethyl-3-hydroxy-indoline-2-one hydrochloride weresuspended in 25 ml of water. To the suspension was added an aqueoussolution of 2.7 grams of potassium cyanate dissolved in 10 ml of water.The mixture thus obtained was stirred at room temperature for 3 hours.At that time, a crystalline substance separated out which was recoveredby filtration and recrystallized from ethanol. The colorless needlesthus obtained had a melting point of2 1 3C.

Elementary analysis of the product gave:

Calculated as C 1-1,, N 0 65.68 5.50 13.15 Found 65.41 5.63 13.71

EXAMPLE 6 Preparation ofl-(p-chlorobenzyl)-3carbamylaminomethyl-3-hydroxy-indoline-2-one 3.4Grams of l-(p-chlorobenzyl)-3-aminomethyl-3- hydroxy-indoline-Z-onehydrochloride were reacted with 2.7 grams of potassium cyanate accordingto the procedure given in Example 5. The colorless needles obtained byrecrystallization of the resulting product had a melting point of 21 3-214C.

Elementary analysis of the needles gave:

C H N Calculated as C H Cl N 0 59.04 g 4.67 12.15 Found 59.31 4.79 12.21

EXAMPLE 7 Preparation of 1-benzyl-3-benzoylaminomethyl-3-hydroxy-indoline-Z-one 2 I 3.0 Grams of1-benzyl-3-aminomethyl-3-hydroxy-indoline-2-one hydrochloride and 7.0grams of benzoyl chloride were suspended in 70 ml of water. To thesuspension under vigorous agitation were added 5.3 grams of sodiumcarbonate. The mixture was stirred for 3 hours at room temperature, andsoon after that,

-crystals separated out which were recovered by filtration andrecrystallized from ethanol. The needles thus obtained had a meltingpoint of l65-167C. Elementary analysis of the needles gave:

C H N Calculated as C H N, 0;: 74.17 5.41 7.52 Found 74.21 5.68 7.43

EXAMPLE 8 Preparation of 1-(p-chlorobenzyl)-3-benzoylaminomethyl-3-hdrox -indoline-2-one 3.4 Grams of -(p-c lorobenzyl)-3-am1nomethyl-3-hydroxy-indoline-Z-one hydrochloride were reacted with 7.0 grams ofbenzoyl chloride and further worked up in accordance with the proceduredisclosed in Example 7. The needles thus obtained had a melting point ofl95-l96C.

Elementary analysis of the needles gave:

C H N Calculated as c, 11,, c1 N 0.: 67.89 4.72 6.89 Found 68.11 4.746.73

EXAMPLE 9 Preparation of l-( p-chlorobenzyl)-3-acetylaminomethyl-3-hydroxy-indoline-2-one 6.0 Grams ofl-(p-chlorobenzyl)-3-aminomethyl-3- hydroxy-indoline-2-one hydrochlorideand 1.8 grams of glacial acetic acid were dissolved in 50 ml of benzene,and the resulting solution was refluxed for 4 hours. After cooling, thecrystalline substance thus formed was recovered byv filtration, and wasthen recrystallized from ethylacetate.

The colorless needles of the product melted at l23-125C.

Elementary analysis of the product gave:

C H N Calculated as C H Cl N; 0 62.70 4.98 8.13 Found 63.02 4.99 7.97

What we claim is:

2. 1-(p-Chlorobenzyl)-3-carbamylaminomethyl-3-hydroxy-indoline-2-one andits pharmacologically acceptable salts. 3.1-Benzyl-3-benzoylaminomethyl-3-hydroxy-indoline-2-one and itspharmacologically acceptable salts. 4.1-(p-Chlorobenzyl)-3-benzoylaminomethyl-3-hydroxy-indoline-2-one and itspharmacologically acceptable salts. 5.1-Benzyl-3-acetylaminomethyl-3-hydroxy-indoline-2-one and itspharmacologically acceptable salts. 6.1-(p-Chlorobenzyl)-3-acetylaminomethyl-3-hydroxy-indoline-2-one and itspharmacologically acceptable salts.